Phenylcyclopropyl carbinols and process for their preparation



United States Patent 3,506,682 PHENYLCYCLOPROPYL CARBINOLS AND PROCESSFOR THEIR PREPARATION John H. Fried, Palo Alto, Calif., assignor toSyntex Corporation, Panama, Panama, a corporation of Panama R ishydrogen, chloro or methyl; and

each of R and R", independent of the other, is hydrogen,

(lower)alkyl, (lower)alkoxy, di-(lower)alkylamino- (lower) alkoxy orcycloalkyleneaminoflower)alkoxy.

N Drawing. Filed Aug. 25, 1966, Ser. No. 574,920 In the context of thepresent invention, the term Int. Cl, C07d 27/00 alkyl, and derivationsthereof such as alkoxy, alkyl- US. Cl. 260-32 6.5 11 Claims ene, and thelike, refer to a branched or straight chain hydrocarbon groups. Whenqualified by the term (lower), such groups will contain up to sixcarbons. Typical ABSTRACT OF THE DISC OS RE of such (lower)alkyl groupsare thus methyl, ethyl, propyl, Thi di l as new compounds, z,4diphenylspiro i-propyl, butyl, hexyl and the like, and of such(lower)alk- [2.5]octan 4 ols, 2-phenyl-4-ethynylspiro[2.5]octan-4- OXYgroups are methoxy, h y, butOXY an th like. ols, 2,4diphenylspiro[2.4]heptan 4 01s, 2 phenyl-4- The term cycloalkyleneaminorefers to a 5 or 6 memethynylspiro[2.4]heptan -4 -ols, 1,2-methylene-1,3,3-t i- 15 bered saturated, nitrogen-containing ring suchas the N- phenylpropan-3-ols, and 1,2-methylene 1,3 diphenyl-3-Pyrrohdmo and N'piperidino p ethynylpropan-B-ols and derivatives thereofwherein the The Compounds of the p ihVehtiOH are ful n h l i i areoptionally Substituted With 1 the control of fertility and in reversingthe effects of estrolk l (l lk diflower)alkylaminouowenalkoxy gen inanimals, thus for instance controlling bulling and orcycloalkyleneamino(lower)alkoxy and wherein the nymphomama in camesomeof these p n s a s h l moiety i Optionally Substituted with chloro ordemonstrate the ability to lower serum cholesterol levels. methyl. Thesecompounds are useful in the control of Generally, these compounds areeflective at a daily dosage fertility, in reversing the eifects ofestrogen in animals, and from Pbout to about 10 P kilogram of inlowering serum cholesterol levels. Also taught are body Welght and y beadministered n C nti nal methods for the preparation of these compoundsand the pharmaflelltical f0rII1S, $\1Ch as tablets, Capsules, Solutions,correspondingintermediate phenyl (or substituted phenyl) suspenslohs h lthehke, pp p for the Particular ll li bi l ful i these preparationsroute of admlnistratlon. In those cases in which one or more of R R andR is an amino function, the compounds are often more suitablyadministered in the form This invention relates to novel organiccompounds and 0 of a nontoxic Pharmaceuticany acceptable acid additionto processes fo h i pwparation salt. For this purpose any of the acidsconventionally More specifically, the present invention pertains to usedin this g Such as hydrochloric, Sulfuric, citric, cyclopropyl carbinols,in particular to 2-phenylcycl0- Phosphoric, p i acetic f the like, y bep y propyl carbinols, and to methods for preparing the same. ThePharmacologwal Properhes of such Salts are however The compoundsprepared in accordance with the presa manifestation of the cationic formof these compounds ent invention may be represented by the followingstruc- 0 the present inv nti n and not Of the salt per se. t l f l Thecompounds of the present invention are prepared R3 from readilyavailable starting materials, or starting ma OH I I OH terials easilyprepared by conventional methods, through 7 a three stage synthesiswhich may be represented as fol- CH2 R2 lows:

R R R R R R A NaOH OHO H2-C-O CH-CCO lR MgX R R R R R R I Mel'zlZnzCu-cno-o on e CH=CCOH CH2 R2 R2 (V) (IV) F in which R is hydrogen,(lower)alkyl, (lower)alkoxy,

di-(lower)alkylamino(lower)alkoxy or cycloalkyleneamino(lower)alkoxy:

In the foregoing R R and R and R are as previously defined. According tothe process of the present inventi'on, benzaldehyde or a substitutedbenzaldehyde (I) and a ketone of Formula II are subjected to a Claisen-Schmidt condensation to yield the n p-unsaturated ketone (III). This isreadily achieved by agitating the two reactants in the presence ofaqueous sodium hydroxide, generally at about room temperature andoptionally in the presence of an alkanol cosolvent. The ketone employedin this reaction may be acetophenone, a substituted acetophenone,cyclohexanone or cyclopentanone.

The a,/3-unsaturated ketone (III) thus obtained is then alkylated,generally through the use of a suitable R is R is hydrogen; R and Rtaken together are oz, fi-butylene; or a, 'y-pr0 pylene Grignard reagentsuch as an alkynylmagnesium bromide, phenylmagnesium chloride, or thelike, preferably in tetrahydrofuran. Alternatively, this alkylation canbe effected with an alkali metal alkyne such as lithium acetylide. Theresultant allylic carbinols (IV) are not only valuable inter-mediate forthe preparation of compounds of the present invention but also exhibitthe same types of activities as do the phenylcyclopropyl carbinolsthemselves.

After isolation, the allylic carbinol (IV) is subjected to the action ofthe reaction product of methylene iodide and a zinc:copper couple inaccordance with the conventional Simmons-Smith reaction conditions. Thusobtained after isolation and purification, is the phenylcyclopropylcarbinol of Formula V.

In those instances in which cyclohexanone or cyclopentanone is employedas the ketone in the initial condensations, the final compounds willhave the structure represented by Formula VIA and VIB respectively,whereas when an acetophenone is employed as the ketone, the finalproduct will have a structure represented by Formula VII:

The compounds of Formula VIA and VIB are herein named as derivatives ofspiro[2.5]octan-4-ol, and spiro [2.4]heptan-4-ol, respectively, whereasthose of Formula VII are named as derivatives of 1,2-methy1enepropan-3-01.

Particularly preferred compounds are those of Formulas VIA, VIB, and VIIwherein R is p-methoxy or p-[fi-(N-pyrrolidinoethoxy)], R i ethynyl,p-methoxyphenyl or p-[B-(N-pyrrolidinoethoxy)]phenyl and R is hydrogenor p-methoxy.

The presence of asymmetric carbon atoms in the compounds of presentinvention permits the existence of optical isomers and all such formsare including within the scope of the present invention. With regard tothe hydroxy substituent n the carbinol carbon atom with reference to thecyclopropane ring, the configuration is The following examples willserve to further typify the nature of the present invention but sincethese are presented solely for the purpose of illustration, they shouldnot be construed as a limitation on the scope of this invention.

EXAMPLE 1 (A) To a stirred solution of 100 g. of sodium hydroxide in oneliter of water and 800* ml. of methanol is added, at room temperature,one-half of the total mixture of 219 g. of4-(N-pyrrolidinoethoxy)benzaldehyde and 100 g. of cyclohexanone. Themixture is stirred vigorously for minutes and the remaining one-half ofthe mixture is then added. Vigorous stirring is continued for anadditional hour and the mixture is then rendered acidic with dilutehydrochloric acid. The aqueous phase is separated, rendered alkalinewith aqueous sodium bicarbonate and extracted with benzene. The combinedorganic layer and benzene extracts are washed well with water, dried andconcentrated to yield2-[4-(N-pyrrolidinoethoxy)benzylidene]cyclohexanone which may be furtherpurified through vacuum distillation or recrystallization from ethylacetate.

(B) A stream of acetylene is bubbled through a suspension of 1.2 molesof ethylmagnesium bromide in freshly distilled tetrahydrofuran for twohours. At the end of this time, the mixture is flushed with dry nitrogenand then treated under nitrogen in a dropwise fashion with 247 g. of2-[4-(N-pyrrolidinoethoxy)-benzylidene] cyclohexanone dissolved in 500ml. of dry tetrahydrofuran. When the addition is complete, the mixtureis refiuxed for one hour, cooled and cautiously treated with water. Thephases are separated and the aqueous layer washed with benzene. Thecombined organic layer and benzene washings are washed with water, driedand concentrated by evaporation to yield 1-ethynyl-2- [4-(N-pyrrolidinoethoxy)benzylidene]cyclohexan 1 01 which may be furtherpurified through recrystallization from, methanol.

(C) A mixture of 70 g. of methylene iodide and 30 g. of zinczcoppercouple in 150 ml. of anhydrous ether is heated under nitrogen at refluxfor three hours. At the end of the time, 20 g. of2-[4-(N-pyrrolidinoethoxy)benzylidene]cyclohexan-1-ol is added to thecooled solution. This mixture is allowed to stand at room temperaturefor two hours and then poured into 2 liters of 2% aqueous sodiumbicarbonate and extracted twice with 100 ml. portions of ethyl ether.These extracted are dried over sodium sulfate and evaporated underreduced pressure. The residue is held at 0.01 mm. to remove anyunreacted methylene iodide and then recrystallized from hexane to yield4 ethynyl 2 [4 (N pyrrolidinoethoxy)phenyl]- spiro[2.5]octan-4-ol.

If cyclopentanone is substituted for cyclohexanone in the procedure ofPart (B) of this example, there is initially obtained 1 ethynyl 2 [4 (Npyrrolidinoethoxy)benzylidene]cyclopentan-l-ol which when treated inaccordance with Part (C) yields4-ethynyl-2-[4-(N-pyrrolidinoethoxy)phenyl]spiro[2.4]heptan-4-o1. 1

EXAMPLE 2 Part (A) of Example 1 is repeated, employing 136 g. ofp-methoxybenzaldehyde in place of 4-(N-pyrrolidinoethoxy) benzaldehyde,to yield 2-(4-methoxybenzylidene)- cyclohexanone.

A solution of g. of 1,2-dichloroethylene in 500 ml. of anhydrous etheris added in a dropwise fashion, under nitrogen and at 0 C., to a stirredsolution of 150 ml. of 1.4 N methyl lithium in anhydrous ether. Afterstirring for an additional minutes at room temperature, a solution of 5g. of 2-(4-methoxybenzylidene)cyclohexanone in 200 ml. of anhydrousether is added in a dropwise fashion with stirring. Stirrin at roomtemperature is continued for 18 hours and the mixture is then pouredinto ice water and extracted with ether. These extracts are washed withwater to neutrality, dried over sodium sulfate and evaporated to yieldl-chloroethynyl-Z-(4-methoxybenzylidene)cyclohexan-l-ol.

Upon subjecting this compound to the action of the reaction product ofmethylene iodide and zinczcopper couple in the fashion described in Part(C) of Example 1, there is obtained 4-chloroethynyl-2-(4-methoxyphenyl)-spiro 2.5 octan-4-ol.

EXAMPLE 3 The 20 ml. of a solution of 284 g. of p-methoxychloro benzene,and 450 ml. of tetrahydrofuran are added under nitrogen, 48.6 g. ofmagnesium turnings, 2 ml. of ethyl bromide and a small iodine crystal.Upon initiation of reaction, the remainder of the p-methoxychlorobenzenetetrahydrofuran solution is added in a dropwise fashion, maintaining thereaction mixture at reflux temperatures. When the magnesium turnings areconsumed, a solution of 618 g. of2-[4-(N-pyrrolidinoethoxy)benzylidene1cyclohexanone in tetrahydrofuranis added in a dropwise fashion, maintaining a nitrogen atmosphere. Uponcompletion of the addition, the mixture is refluxed for one hour,cooled, and cautiously treated with a saturated aqueous solution ofammonium chloride. The layers are separated and the aqueous layer isrendered alkaline and extracted with benzene. These extracts arecombined with the organic layer and this combined mixture is washed withwater, dried over sodium sulfate and evaporated to yield 1 (4methoxyphenyl) 2 [4 (N pyrrolidinoethoxy)benzylidene]cyclohexan-l-olwhich may be further purified through recrystallization from methanol.

Upon subjecting this compound to the procedure of Part (C) of Example 1,there is obtained 4-(4-methoxyphenyl) 2 [4 (Npyrrolidinoethoxy)phenyl]spiro- [2.5]octan-4-ol.

EXAMPLE 4 p-Methoxybenzaldehyde and 4-(N-pyrrolidinoethoxy)-acetophenone are.allowed to react in the presence of sodium hydroxide inthe manner described in Part (A) of Example 1 to yield, upon completionof the procedure therein described, 1 (4 methoxyphenyl) 3 [4 (N-pyrrolidinoethoxy)phenyl]propen-3-one. Upon treatment of this compoundwith phenyl magnesium chloride or phenyl-magnesium bromide as describedin Example 3, there is obtained 1-(4-methoxyphenyl)-3-phenyl-3-[4-(N-pyrrolidinoethoxy)phenyl]propen-3-ol. This compound is then treated withthe reaction product of methylene iodide and zinczcopper couple asdescribed in Part (C) of Example l to yield 1,2-methylene-1-(4methoxyphenyl)-3- phenyl-3- [4- N-pyrrolidinoethoxy phenyl] propan-3-ol.

By employing ethynylmagnesium bromide in place of phenylmagnesiumchloride, there is obtained 1,2-methylene 1 (4 methoxyphenyl) 3 ethynyl3 [4 (N- pyrrolidinoethoxy) phenyl] propan-3-ol.

EXAMPLE 5 In a similar fashion as described above, by condensing thefollowing aldehydes and ketones, treating the resulting unsaturatedketones with the indicated Grignard reagents, and subjecting thethus-produced unsaturated carbinols with the reaction product ofmethylene iodide and zinc: copper couple, the following cyclopropylcarbinols are respectively obtained.

(I) Aldehyde:

(a) benzaldehyde (b) 3-methoxybenzaldehyde (c) 4-methoxybenzaldehyde (d)4-methoxybenzaldehyde (e) 4-methoxybenzaldehyde (f)4-methoxybenzaldehyde (II) Ketone:

(a) cyclohexanone (b) cyclohexanone (c) 4-methoxyacetophenone (d)3-methylacetophenone (e) cyclopentanone (f) cyclopentanone (III)Grignard reagent:

(a) 4-methoxyphenylmagnesium bromide (b) 3-methylphenylmagnesium bromide(c) prop-l-enylmagnesium bromide (d) 4 (N,Ndiethylaminoethoxy)phenylmagnesium bromide (e) 4-methoxyphenylmagnesiumbromide (f) lithium acetylide 6 (IV) Product:

(21) 4 (4 methoxyphenyl) 2 phenylspiro[2.5]-

octan-4-ol (b) 4 (3 methylphenyl) 2 (3 methoxyphenyl)-spiro[2.5]octan-4ol (0,) 1,2 methylene 1,3 bis(4 methoxyphenyl)-3-(prop-1-ynyl)propan-3-ol ,(d) 1,2 methylene 1 (4 methoxyphenyl) 3- (3methylphenyl) 3 '[4 (N,N diethylaminoethoxy)phenyl]propan-3-ol (e) 2,4bis(methoxyphenyl) spiro[2.4]cycloheptansa4-ol (f) .2 (4 methoxyphenyl)4 ethynylspiro[2.4]-

cycloheptan-4-ol What is claimed is: 1. The compound of formula:

CH2 R wherein R is hydrogen, (lower) alkyl, (lower)alkoxy, di-(lower)alkylarnino(lower)alkoxy, or cycloalkylenearnino (lower) alkoxy;

R is-CECRE or- R is- R is hydrogen;

R and R taken together are a,6-butylene or orgy-propylene;

R is hydrogen, chloro or methyl, and;

each of R and R is hydrogen, (lower)alkyl, (lower)- alkoxy,di(lower)alkylamino(lower)alkoxy or cycloalkyleneamino (lower) alkoxy.2. The compound of the formula:

wherein R is hydrogen, (lower)alkyl, (lower)alkoxy, di-(lower)alkylamino (lower) alkoxy, or cycloalkyleneamino(lower)alkoxy andR is hydrogen, chloro or methyl.

3. The compound according to claim 2 wherein R is p-methoxy,p-[di(1ower)alkylaminoethoxy] or p-(N-pyrrolidinoethoxy) and R ishydrogen or chloro.

4. The compound of the formula:

wherein each of R and R is hydrogen, (lower)alkyl, (lower)alkoxy,di(lower)alkylamino (lower)alkoxy or cycloalkyleneamino (lower) alkoxy.

5. The compound according to claim 4 wherein each of R and R isp-methoxy, p-[di-(lower)alkylaminoethoxy] or p-(N-pyrrolidinoethoxy).

7 6. The compound of the formula:

CHCH(IJOH e Q- Cz CECR wherein each of R and R is hydrogen,(lower)a1kyl, (lower) alkoxy, di(lower) alkylaminoflower) alkoxy orcycloalkyleneamino(lower)a1koxy; and R is hydrogen, chloro or methyl.

8. 4 ethynyl 2 [4 (N-pyrrolidinoethoxy)phenyl]- spiro[2.5 ]octan-4-o1.

9. 4-(4-methoxyphenyl)-2-[4-(N pynrolidinoethoxy)- phenyl] spiro [2.5octan-4-ol.

10. 1,2 methylene 1 (4 methoxyphenyl)3-phenyl-3-[4-N-pyrrolidinoethoxy)phenyl]propan-3-ol.

11. 1,2 methylene 1 (4 methoxyphenyl)-3-ethynyl-3- [4-(N-pyrrolidinoethoxy phenyl] propan-3-ol.

References Cited Biro et al.: Helv. Chim. Acta., vol. 37, pages 2230 to2239 (1954).

Goffinet: Comptes Rendus, vol. 239, pages 1815 to 1817 (1954).

Darby et aL: J. Org. Chem., vol. 22 pages 1353 to 1354 (1957 ChemicalAbstracts, vol. 57, cols. 16508 to 16509 (1962).

Ziegler et al.: Ber. Deut. Chem., vol. 55, pages 2257 to 2259 and 2271to 2272 (1922).

Luttrinhaus: Ber. Deut. Chem., vol. 67, pages 1602 to 1603 (1934).

JOHN D. RANDOLPH, Primary Examiner US. Cl. X.R.

